1. Field of the Invention
The present invention relates to the use of chelating agents and their metal chelates and to the use of certain manganese containing compounds, in particular manganese chelates, in medicine. In particular, the invention relates to the use of such compounds in anti-tumour therapy.
2. Description of the Related Art
A number of anti-tumor agents are associated with adverse side-effects which severely limit their widespread use. Paclitaxel or taxol is one such agent which has shown anti-neoplastic action against a variety of malignant tissues, including those of the breast, colon, lung and ovary as well as in malignant melonoma. However, at the high dosages required to have an anti-neoplastic effect, paclitaxel has a number of adverse side-effects which can include cardiovascular irregularities as well as hematological and gastrointestinal toxicity.
Anthracycline antibiotics, such as doxorubicin (adriamycin), are amongst the most important of the anti-tumour agents. However, their clinical value is limited by their cardiotoxicity, which manifests itself as congestive heart failure in 15-40% of patients undergoing therapy. The most likely mechanism for their toxicity is believed to be the production of oxygen-derived free radicals in the heart, which cause membrane damage and mitochondrial damage in metabolically active tissues such as heart muscle and intestinal mucosa.
There is evidence to suggest that cardiac damage during anthracycline therapy can be reduced by simultaneous administration of the iron chelator, dexrazoxane (Goodman & Gilman, 9th ed. 1233-1287 (1996)). However, dexrazoxane and its analogues have been found to be toxic and as a result can only be used in relatively low dosages.
It will be appreciated that there thus exists a continuing need for compounds which are able to act as chemoprotectants during anti-cancer therapy.
In particular, there exists the need for an effective chemoprotectant which in reducing the toxic side effects of the anti-tumour agent, will permit higher, more effective doses of the anti-tumour agent to be administered.
The medical use of chelating agents and their metal chelates is well established, for example in diagnostic techniques such as X-ray, magnetic resonance imaging (MRI) ultrasound imaging or scintigraphy. A wide variety of chelating agents and metal chelates are known or have been described.
Aminopoly (carboxylic acid or carboxylic acid derivative) chelating agents and their metal chelates are well known and are described for example in EP-A-299795, EP-A-71564, DE-A-3401052, EP-A-203962 and EP-A-436579.
Dipyridoxyl based chelating agents and their chelates with trivalent metals have been described by Taliaferro (Inorg. Chem. 23: 1183-1192 (1984)). The compound N,N'-dipyridoxyl ethylenediamine-N,N'-diacetic acid (PLED) has been evaluated as a chelating agent for the preparation of gallium or indium containing radiopharmaceuticals (see Green et al. Int. J. Nucl. Med. Biol, 12(5): 381-386 (1985)).
A number of PLED derivatives and analogues have also been described for use in MRI contrast media, in particular the chelating agent N,N'-bis-(pyridoxal-5-phosphate)-ethylenediamine-N,N'-diacetic acid (DPDP) and its manganese (II) chelate, Mn DPDP (see EP-A-290047 and EP-A-292761).